Sequence logic at enhancers governs a dual mechanism of endodermal organ fate induction by FOXA pioneer factors

Ryan J. Geusz, Allen Wang, Dieter K. Lam, Nicholas K. Vinckier, Konstantinos-Dionysios Alysandratos, David A. Roberts, Jinzhao Wang, Samy Kefalopoulou, Araceli Ramirez, Yunjiang Qiu, Joshua Chiou, Kyle J. Gaulton, Bing Ren, Darrell N. Kotton and Maike Sander ()
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Ryan J. Geusz: University of California, La Jolla
Allen Wang: University of California, La Jolla
Dieter K. Lam: University of California, La Jolla
Nicholas K. Vinckier: University of California, La Jolla
Konstantinos-Dionysios Alysandratos: Center for Regenerative Medicine of Boston University and Boston Medical Center
David A. Roberts: Center for Regenerative Medicine of Boston University and Boston Medical Center
Jinzhao Wang: University of California, La Jolla
Samy Kefalopoulou: University of California, La Jolla
Araceli Ramirez: University of California, La Jolla
Yunjiang Qiu: University of California, La Jolla
Joshua Chiou: University of California, La Jolla
Kyle J. Gaulton: University of California, La Jolla
Bing Ren: University of California, La Jolla
Darrell N. Kotton: Center for Regenerative Medicine of Boston University and Boston Medical Center
Maike Sander: University of California, La Jolla

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract FOXA pioneer transcription factors (TFs) associate with primed enhancers in endodermal organ precursors. Using a human stem cell model of pancreas differentiation, we here discover that only a subset of pancreatic enhancers is FOXA-primed, whereas the majority is unprimed and engages FOXA upon lineage induction. Primed enhancers are enriched for signal-dependent TF motifs and harbor abundant and strong FOXA motifs. Unprimed enhancers harbor fewer, more degenerate FOXA motifs, and FOXA recruitment to unprimed but not primed enhancers requires pancreatic TFs. Strengthening FOXA motifs at an unprimed enhancer near NKX6.1 renders FOXA recruitment pancreatic TF-independent, induces priming, and broadens the NKX6.1 expression domain. We make analogous observations about FOXA binding during hepatic and lung development. Our findings suggest a dual role for FOXA in endodermal organ development: first, FOXA facilitates signal-dependent lineage initiation via enhancer priming, and second, FOXA enforces organ cell type-specific gene expression via indirect recruitment by lineage-specific TFs.

Date: 2021
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DOI: 10.1038/s41467-021-26950-0

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